Constant release rate solid oral dosage formulations of quinidine

ABSTRACT

A constant order release rate solid oral dosage formulation of quinidine or a pharmaceutically acceptable salt thereof, said formulation comprising: a therapeutically effective amount of quinidine or a pharmaceutically acceptable salt; from about 0.5 to 6.0 weight percent of an acid-retardant or hydrophobic cellulose derivative; from about 2.5 to 35 weight percent of a hydrogenated vegetable oil: from about 1 to 20 weight percent of an acrylic acid polymer; from about 0.5 to 4.0 weight percent of fumed silicon dioxide and from about 0.4 to 3.0 percent of a lubricant.

This is a division of application Ser. No. 455,192 filed Jan. 3, 1983.

BACKGROUND OF THE INVENTION

The present invention relates to improved pharmaceutical formulationsand more specifically relates to constant release rate solid oral dosageformulations of quinidine or a pharmaceutically acceptable salt thereof.

It is an axiom in pharmaceutical science than in order for a drug in anoral solid dosage formulation to be absorbed, it must first becomesoluble in the aqueous media of the stomach or small intestine. Productswhich are rapidly dissolved in water are also rapidly absorbed into thebody. For such products, controlling their rate of solvation afteringestion also influences their rate of absorption, and drugs which arehighly or moderately water-soluble present special formulation problems.

Formulations which effectively control the rate of solvation of highlywater-soluble drugs are disclosed and claimed in commonly assigned,copending U.S. patent applications Ser. No. 443,397, filed Oct. 8, 1982.See also commonly assigned, copending U.S. Pat. applications Ser. No.364,014 filed Mar. 31, 1982 for constant order release theophyllineformulations, allowed U.S. Ser. No. 366,594, filed Apr. 8, 1982 forconstant order release aspirin formulations and U.S. Ser. No. 334,124filed Dec. 24, 1981 for constant release indomethacin formulations. Theabove commonly assigned, copending application discloses constant orderrelease solid oral dosage formulations which provide a smooth onset ofdrug action with a subsequent longer duration of pharmacologicalactivity and avoid the peaks and valleys of activity and side effects ofdrugs administered in conventional formulations, including conventionaltimed-release formulations. It was also recognized that in view of thenumber of factors which successfully overcomes the properties peculiarto a specific drug or a group of drugs which share given properties,simply is not suitable for all drugs for the following reasons.

A second factor influencing drug absorption after solubility hasoccurred is the passage of the drug across the intestinal membrane. Adrug generally crosses several membranes to reach its receptor site.This transfer is usually accomplished by passive diffusion. Specialtransport mechanisms such as facilitated diffusion and active transportallow somes substances to cross cell membranes at a faster rate thansimple diffusion. By far, however, the most common mechanism fortransport of a drug in solution across the intestinal wall is by passivediffusion.

Passive diffusion is characterized by the movement of the drug moleculedown a concentration or electrochemical gradient without the expenditureof cellular energy. The transfer process is neither saturable norinhibited by other materials and is only slightly sensitive totemperature changes. Since most cells in the gastrointestinal tract arein close proximity to capillaries, the passage of drugs across shortdistances is usually rapid.

The driving force for passive drug transport is the difference betweenthe concentration of the diffusing drug in the intestinal tract and theconcentration gradient of the drug on the other side of the plasmamembrane. The rate of drug penetration corresponds to the concentrationgradient and is characterized by Fick's law.

Many drugs are either an organic acid or a base. Acids donate a hydrogenion to form a negatively charged anion, while bases accept a hydrogenion to form a positively charged cation. It is usually assumed that onlynonionized, lipid-soluble drugs pass through the lipid rich membranes ofthe intestinal tract. The ionized molecule is thought to be too polar topenetrate this lipoidal barrier. If it does cross the cell wall, it doesso at a slow rate. This concept of drug absorption is known as nonionicdiffussion.

An extension of this theory is the pH partition hypothesis, whichasserts that the passage rate of a drug through a membrane is dependentupon the pH of the drug's enviroment and the dissociation constant, or"pK_(a) " of the drug. The pK_(a) is expressed as the pH at which 50% ofthe drug will be in the ionized form and 50% will be in the nonionizedform. Diffusion of acids and bases across the membrane is not alwaysinfluenced by pH, as in the case of weak acids or bases. These types ofproducts are essentially completely nonionized at all physiologic pHvalues. At the other extreme however, are strong acids and bases whichare almost completely ionized, and their transfer is dependent upon thepH at which they become dissolved and subsequently becomc ionized ornonionized.

An example of pH partition hypothesis may be explained by the fact thataspirin, which has a pk_(a) or dissociation constant of between 3 and3.7 becomes very nonionized in the acid media of the stomach andsubsequently is rapidly absorbed from the gastric mucosa, where the pHis between 1 and 3. As the drug particles pass into the small intestineswhere the pH increases and the rate of ionization is changed soabsorption is subsequently slowed. Conversely strong bases such asephedrine, which has a pK_(a) of 9.3, or amphetamine with a pK_(a) of9.9 are almost negligibly absorbed from the acidic gastric contents, butare absorbed rather rapidly from the intestinal fluid which has a muchlower hydrogen ion concentration. By controlling the release of a drugfrom the tablet matrix one can control the rate of solvation. The rateof absorbtion for those products having a pK_(a) above 7 will begreatest, once they reach the small intestine.

While the pH partition hypothesis and nonionic diffusion cannot entirelyaccount for drug absorbtion, however it is one factor to consider amongthe various factors controlling the rate and mechanism of drugabsorbtion in the instestinal tract.

The present invention provides formulations for drugs with a basicnature ie: pk_(a) 7-10. The formulations of the present inventionrelease their contents in a rather constant manner in the smallintestine, thereby controlling the rate at which passive diffusion canoccur. While commonly assigned, co-pending U.S. patent application Ser.Nos. 443,497; 364,014; 366,594 and 334,124 disclose various constantrelease formulations, the present invention provides formulations whichtake into account the pH partition and which will release basic drugsinto the small intestines at a constant and controlled rate, therebycontrolling their serum level and prohibiting the peaks and valleys orerratic absorbtion which may be obtained with standard formulations.

SUMMARY

This invention provides constant order formulations of thecardiovascular agent quinidine or a pharmaceutically acceptable saltthereof. Quinidine has a water solubility of 100 gm/ml.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention provides a constant order release, solid oraldosage formulation of the cardiovascular drug quinidine or apharmaceutically acceptable salt thereof, said formulation comprising atherapeutically effective amount of said drug, the drug particles beingcoated with from about 2.5 to about 6 weight percent of anacid-retardant cellulose derivative, preferably from 0.8 to 4.6 weightpercent; in a lipid-polymer matrix. The lipid comprises from 2.5 to 35.0weight percent of the composition, preferably between 7.0-25.0 weightpercent. The preferred lipids are hydrogenated vegetable oil and thepreferred hydrogenated vegetable oil is a hydrogenated cotton seed oilsold under the mark LUBRITAB by E. Mendell Corporation. The preferredacid polymer is an acrylic acid polymer, carboxypolymethylene (carbomer)sold under the trademark CARBOPOL-934-P by B. F. Goodrich. The acidpolymer is present in amounts ranging from 1 to 20 weight percent of theformulation, preferably from about 2.5 to 12 weight percent. Thecomposition of the present invention additionally comprises ananti-sticking agent, preferably fumed silicon dioxide sold under themark SYLOID-244 by W. Grace Company in amounts of between 0.5-4.0 weightpercent of the composition and from 0.4 to 3.0 weight percent of atabletting lubricant such as magnesium stearate, talc, stearic acid andthe like.

The preferred acid-retardant and hydrophobic cellulose derivativesinclude, but are not limited to, cellulose acetate phthalate,hydroxypropylmethyl cellulose phthalate, ethylcellulose and the like.Such agents are well known in the art.

In addition, the formulations of the present agent may optionallyinclude bulking agents and disintegrants, depending upon the desiredrelease characteristic of the finished product. Such agents areoptional, and not critical to the present formulations.

The formulations of this invention retard the release of the active drugin the gastric juices where there is a low pH and subsequently therewould be a high degree of nonionized material available, which wouldresult in rapid absorption of the drug product. Controlling the drugrelease is accomplished by the incorportion of an acid resistantcellulose derivative perferably cellulose actate phthalate orhydroxypropylmethyl cellulose phthalate into the formulation.

The lipid complex component of the present formulation slows thesolvation rate of the drug as it enters the more neutral to akalinemedia of the small intestine. Although there will be a shift in thedissociation constant producing more ionized drug, the incorporation ofthe drug product into a lipid material offsets the changes indissociation constant facilitating the absorption of the ionizedfragments by the inherent lipophilicity of the solvated material. Thislipid content also controls the rate of drug release from the tabletmatrix further assuring a controlled and constant release rate product.By utilizing a hydrophosic cellulose derivative the rate of drugdissolution and solvation is also controlled.

It is important to note that compositions containing polymers of acrylicacid in conjunction with hydrogenated vegetable oil 20 are mechanicallydifficult to press into a tablet without considerable weight variationin the tablets or sticking to the tablet punches. The classicaltabletting lubricants such as talc, magnesium stearate, stearic acid,cetyl alcohol, calcium stearate or zinc stearate are ineffective in 25alleviating this problem. It was found that the only suitable solutionto the problem was the inclusion of 0.5 to 4.0 weight percent of fumedsilicon dioxide, sold under the trademark SYLOID-244 by W. GraceCompany. This both alleviates the problem of tablet sticking and servesas 30 superior lubricant.

Turning to the preferred process of the present invention, all materialsare weighed and blended for 15 minutes for each 40 kilograms of drymaterial. Isopropyl alcohol which may constitute 35-60 weight percent isslowly added at a rate of 3 minutes per liter of solvent. Ifethylcellulose is to be dispersed in the solvent prior to granulation,the cellulose derivative should be blended until there is completedispersion and clarity of the solution. Generally, it will take between35-40 minutes per 125 liters of fluid using a lightening blender toeffect complete dispersion and solvation of the ethylcellulose. It iscritical that the wet granulation be completely dried before screening.Failure to observe this technique may result in rupture of the granulesand a loss of the constant release rate profile of the resultingtablets. In conventional prior art methods, the wet granulations aregenerally screened immediately after formation, then dried. If the priorart processes are employed, the constant release rate profile of thetablets may be destroyed.

When cellulose acetate phthalate is employed in formulations of thepresent invention, it is important to granulate the drug and celluloseacetate phthalate, and/or bulking agent or disintegrant if such agentsare employed, with the solvents and subsequently add the remainder ofthe ingredients. Otherwise, a viscous, rubbery mixture which cannot betabletted will be obtained.

The following examples further illustrate the present invention.

EXAMPLE 1

Quinidine sulfate tablets weighing 362 mg are prepared from thefollowing formulation:

    ______________________________________                                        1.     Quinidine Sulfate     300    gm                                        2.     Hydrogenated Cotton seed oil                                                                        25     gm                                        3.     Carbopol - 934p       10     gm                                        4.     Microcrystalline cellulose                                             5.     Cellulose acetate phthalate                                                                         9      gm                                        6.     Syloid 244            10     gm                                        7.     Magnesium stearate    5      gm                                        8.     Methylene chloride    25     ml                                        9.     Isopropyl alcohol     100    ml                                                                     362    gm                                        ______________________________________                                    

In the above formulation quinidine sulfate, dibasic calcium phosphate,and microcrystalline cellulose are blended in a Hobart mixer. Thecellulose acetate phthalate is dissolved in methylene chloride andisopropyl alcohol until a clear solution is achieved. The dry blend isthen granulated with the solvent-cellulose solution until a well formedgranulate is produced. The product is dried at 100° F. and then passedthrough a #18 mesh screen blended with magnesium stearate and compressedinto capsule-shaped tablets weighing 362 mg, with a hardness of 10-12kp. These tablets were then placed in a standard U.S.P. disintegrationapparatus without discs and a gastric solution with a pH of 1.2-1.4. Theamount of mean weight loss in 6 tablets over 3 hours in shown below.

    ______________________________________                                        DISINTEGRATION % pH 1.2-1.4                                                           0 HR  1 HR       2 HR     3 HR                                        ______________________________________                                        1.        414 mg  410        407    400                                       2.        416 mg  412        406    398                                       3.        412 mg  406        405    399                                       4.        413 mg  408        402    392                                       5.        417 mg  412        409    389                                       6.        414 mg  410        403    395                                       mean      414.3   409.6      405.3  395.5                                     S.D.+     1.86    2.3        2.6    4.3                                       % Loss    0       1.13%      2.2%   4.8%                                      ______________________________________                                    

This demonstrates that after 3 hours of agitation in gastric acid mediathe tablets lost less than 5% of their weight.

Tablets from this same batch were tested for dissolution using a U.S.P.apparatus II at 50 rpm and pH 7.5. The following are the results fromthat test expressed as % of drug dissolved:

    ______________________________________                                        DISSOLUTION                                                                   % OF DRUG DISSOLVED                                                           1 HR        2 HR    3 HR    4 HR   5 HR  6 HR                                 ______________________________________                                        1.     23%      31%     42%   56%    62%   75%                                2.     25%      30%     43%   52%    65%   73%                                3.     26%      29%     44%   53%    61%   76%                                4.     22%      33%     46%   55%    67%   77%                                5.     19%      32%     41%   51%    60%   74%                                6.     21%      31%     40%   54%    63%   72%                                mean % 22.7%    31.0%   42.7% 53.5%  63.0% 74.5%                              S.D.+  2.58     1.40    2.16  1.87   2.61  1.87                               ______________________________________                                    

This study demonstrates the behavior of the tablets in a more neutral toakaline media. Using linear regression analysis on the aboveinformation, a constant release rate pattern is demonstrated. Thecorrelation coefficent(r value) slope and intercept are shown below.

ANALYSIS BY LINEAR REGRESSION

r=0.999

slope=0.096

intercept=-1.076

EXAMPLE 2

Quinidine sulfate tablets weighing 430 gm are prepared from thefollowing formulation.

    ______________________________________                                        1.     Quinidine sulfate     300    gm                                        2.     Hydrogenated cotton seed oil                                                                        100    gm                                        3.     Carbopol-934P         10     gm                                        4.     Ethylcellulose (100 cps)                                                                            10     gm                                        5.     Fumed silicon dioxide 5      gm                                        6.     Magnesium stearate    5      gm                                        7.     Isopropyl alcohol     100    gm                                                                     430    gm                                        ______________________________________                                    

The quinidine, hydrogenated cotton seed oil and microcrystallinecellulose are blended. Ethycellulose is dissolved with agitation inisopropyl alcohol. After complete dispersion, the solvent-cellulosesolution is used to granulate the quinidine, cottonseed oil andmicrocrystalline cellulose. After a granulate is formed it is completelydried at 100° F., passed through a #18 mesh screen and compressed intotablets weighing 430 mg containing 300 mg of quinidine sulfate with ahardness of 10-12 kp.

EXAMPLE 3

Hydralazine tablets weighing 580 mg and containing 400 mg of active drugare prepared from the following formulation.

    ______________________________________                                        1.     Hydralazine hydrochloride                                                                           400    gm                                        2.     Lactose               40     gm                                        3.     Hydrogenated cotton seed oil                                                                        100    gm                                        4.     Carbopol 934-P        20     gm                                        5.     Microcrystalline cellulose                                                                          10     gm                                        6.     Fumed silicon dioxide 7      gm                                        7.     Magnesium stearate    3      gm                                        8.     Isopropyl alcohol     250    gm                                                                     580    gm                                        ______________________________________                                    

Hydralazine, lactose, hydrogenated cottonseed oil Carbopol 934-P andmicrocrystalline cellulose are placed in a Hobart mixer and throughlyblended. A wet granulation is then made by adding slowly the isopropylalcohol while blending. After a granulate is formed, it is air dried at100° F. and passed through a number #16-#18 mesh screen and blended withthe silicon dioxide and magnesium stearate. Tablets are then compressedfrom the granulate to form a capsule shaped tablet weighing 580 mg andcontaining 400 mg of hydralazine. The tablets have a hardness of 10-12kp.

EXAMPLE 4

Hydralazine tablets weighing 530 mg and containing 200 mg of active drugare prepared from the following formulation.

    ______________________________________                                        1.    Hydralazine hydrochloride                                                                             200    gm                                       2.    Lactose                 75     gm                                       3.    Hydrogenated cotton seed oil                                                                          100    gm                                       4.    Carbopol 934-p          20     gm                                       5.    Cellulose acetate phthalate                                                                           25     gm                                       6.    Microcrystalline cellulose                                                                            50     gm                                       7.    Fumed silicon dioxide (Syloid-244)                                                                    6      gm                                       8.    Magnesium Stearate      4      gm                                       9.    Methylene Chloride      75     ml                                       10.   Isopropyl alcohol       150    ml                                                                     530    gm                                       ______________________________________                                    

Hydralazine, lactose, diliasic calcium phosphate, Carbopol 934-P andmicrocrystalline cellulose are throughly blended in a Hobert mixer. Thecellulose acetate phthalate is dissolved in methylene chloride andisopropyl alcohol until a clear solution is obtained, it is then addedin a slow steady stream to the blended dry mixture until an overwetgranule is formed. The granule is air dried at 100° F. and then passedthrough a #18 screen, mixed throughly with the silicon dioxide andmagnesium stearate. Following this blending the granulate is compressedinto tablets weighing 530 mg and containing 200 mg of hydralazine. Thetablets have a hardness of 10-12 kp.

Tablets prepared according to the method of example 4 were placed in aUSP disintegration apparatus with the fluid media being 1.2-1.4. After 3hours of agitation there was less than a 10% reduction in tablet weight.Six tablets were randomly selected for dissolution testing in USPapparatus II at 50 r.p.m. and pH 7.5. The following results wereobserved:

    ______________________________________                                        DISSOLUTION % HYDRALAZINE DISSOLVED                                                   1 HR  2 HR       3 HR    4 HR                                         ______________________________________                                        1.        20      51         70    93                                         2.        22      57         76    99                                         3.        19      49         68    95                                         4.        24      58         75    98                                         5.        26      56         73    96                                         6.        21      54         71    97                                         Mean       22%    54.2%      72.2% 96.3%                                      S.D.+     2.61    3.54       3.06  2.16                                       ______________________________________                                    

ANALYSIS BY REGRESSION

r=0.994

slope=0.041

Intercept=-0.007

EXAMPLE 5

Tablets weighing 488 mg and containing 250 mg of verapamil are preparedfrom the following formulation.

    ______________________________________                                        1.    Verapamil hydrochloride 250    gm                                       2.    Lactose                 50     gm                                       3.    Hydrogenated cotton seed oil                                                                          75     gm                                       4.    Microcrystalline Cellulose                                                                            10     gm                                       5.    Carbopol 934-P          70     gm                                       6.    Ethycellulose (100 cps) 10     gm                                       7.    Hydroxypropylmethyl cellulose                                                                         15     gm                                       8.    Fumed silicon dioxide (Syloid 244)                                                                    5      gm                                       9.    Magnesium stearate      3      gm                                       10.   Isopropyl alcohol       200    ml                                                                     488                                             ______________________________________                                    

Ingredients 1-5 are dry blended. Ethycellulose and hydroxypropylmethylcellulose are disolved in 200 ml isopropyl alcohol and the blendedpowders are wet granulated. After the granulate is formed it is dried at100° F. and then passed through a #18 screen, compressed into tabletsweighing 488 mg with hardness of 10-12 kp.

EXAMPLE 6

Tablets containing 250 mg of verapmil and weighing 505 mg are preparedfor the following formulation.

    ______________________________________                                        1.     Verapamil hydrochloride                                                                             250    gm                                        2.     Hydrogentated cotton seed oil                                                                       100    gm                                        3.     Carbopol 934-p        70     gm                                        4.     Lactose               50     gm                                        5.     Microcrystalline cellulose                                                                          20     gm                                        6.     Fumed silicon dioxide 10     gm                                        7.     Magnesium stearate    5      gm                                        8.     Isopropyl alcohol     200    ml                                                                     505    gm                                        ______________________________________                                    

Ingredients 1-5 are dry blended in Hobart mixer. Isopropyl alcohol isslowly added to form a wet granulation. The Granulate is then air driedat 100° F., passed through a #16 mesh screen and compressed into tabletsweighing 505 mg and containing 250 mg of verapamil, hardness 10-12 kp.

EXAMPLE 7

Verapamil tablets weighing 436 mg and containing 250 g of active drugare prepared from the following formulation.

    ______________________________________                                        1.     Verapamil hydrochloride                                                                            250    gm                                         2.     Lactose              50     gm                                         3.     Dibasic calcium phosphate                                                                          100    gm                                         4.     Microcrystalline cellulose                                                                         20     gm                                         5.     Cellulose acetate phthalate                                                                        10     gm                                         6.     Syloid - 244         3      gm                                         7.     Talc                 3      gm                                         8.     Isopropyl Alcohol    50     ml                                         9.     Methylene chloride   50     ml                                                                     436    gm                                         ______________________________________                                    

Ingredients 1-4 are dry blended in Hobart mixer. Cellulose acetatephthalate is dissolved in a mixture of methylene chloride and isopropylalcohol, after complete dispersion powders are wet granulated with thecellulose mixture. The granules are air dried at 100° F. and passedthrough #18 screen, blended with stearic acid and talc and compressedinto tablets weighing 436 mg and with a hardness of 10-12 kp.

EXAMPLE 8

Tablets containing 250 mg of propranolol and weighing 488 mg areprepared from the following formulation.

    ______________________________________                                        1.    Propranolol hydrochloride                                                                             250    gm                                       2.    Hydrogenated cotton seed oil                                                                          50     gm                                       3.    Lactose                 50     gm                                       4.    Dibasic calcium phosphate                                                                             75     gm                                       5.    Microcrystalline Cellulose                                                                            10     gm                                       6.    Carbopol 934-P          20     gm                                       7.    Ethycellulose (100 cps) 10     gm                                       8.    Hydroxypropylmethyl cellulose                                                                         15     gm                                       9.    Fumed silicon dioxide (Syloid 244)                                                                    5      gm                                       10.   Magnesium stearate      3      gm                                       11.   Isopropyl alcohol       200    ml                                                                     488                                             ______________________________________                                    

Ingredients 1-6 are dry blended. Ethycellulose and hydroxypropylmethylcellulose are dissolved in 200 ml isopropyl alcohol and the blendedpowders are wet granulated. After the granulate has formed, it is driedat 100° F. and then passed through a #18 mesh screen, and compressedinto tablets weighing 488 mg with hardness of 10-12 kp.

EXAMPLE 9

Propanolol tablets weighing 505 mg and containing 250 mg of active drugare prepared from the following formulation.

    ______________________________________                                        1.     Propranolol hydrochloride                                                                           250    gm                                        2.     Hydrogenated cotton seed oil                                                                        100    gm                                        3.     Carbopol 934-P        70     gm                                        4.     Lactose               50     gm                                        5.     Microcrystalline cellulose                                                                          20     gm                                        6.     Fumed silicon dioxide 10     gm                                        7.     Magnesium stearate    5      gm                                        8.     Isopropyl alcohol     200    gm                                                                     505    gm                                        ______________________________________                                    

Ingredients 1-5 are dry blended in a Hobart mixer. Isopropyl alcohol isslowly added to form wet granulation. The granulate is then air dried at100° F., passed through a #16 mesh screen and compressed into tabletshaving a hardness at 10-12 kp.

I claim:
 1. A constant order release solid oral dosage formulation ofquinidine or a pharmaceutically acceptable salt thereof, saidformulation comprising: a therapeutically effective amount of quinidineor a pharmaceutically acceptable salt thereof; from about 0.5 to 6.0weight percent of one or more cellulose derivatives selected from thegroup consisting of cellulose acetate phthalate,hydroxypropylmethylcellulose, ethyl cellulose, and microcrystallinecellulose; from about 2.5 to 35 weight percent of a hydrogenatedvegetable oil; from about 1 to 20 weight percent ofcarboxypolymethylene; from about 0.5 to 4.0 weight percent of fumedsilicon dioxide and from about 0.4 to 3.0 weight percent of a tablettinglubricant.
 2. The formulation of claim 1 wherein said cellulosederivative is a combination of cellulose acetate phthalate andmicrocrystalline cellulose.
 3. The formulation of claim 1 wherein saidhydrogenated vegetable oil is hydrogenated cottonseed oil.
 4. Theformulation of claim 1 wherein said cellulose derivative is ethylcellulose.
 5. The formulation of claim 1 wherein said cellulosederivative is a combination of cellulose acetate phthalate andmicrocrystalline cellulose, and said hydrogenated vegetable oil ishydrogenated cottonseed oil.
 6. The formulation of claim 1 wherein saidcellulose derivative is ethyl cellulose and said hydrogenated vegetableoil is hydrogenated cottonseed oil.
 7. A constant order release solidoral dosage formulation of quinidine or a pharmaceutically acceptablesalt thereof comprising: a therapeutically effective amount of quinidineor a pharmaceutically acceptable salt thereof; from 0.5 to 6.0 weightpercent of a combination of microcrystalline cellulose and celluloseacetate phthalate; from about 2.5 to 35 weight percent of a hydrogenatedvegetable oil; from about 1 to 20 weight percent ofcarboxypolymethylene; from about 0.5 to 4.0 weight percent of fumedsilicon dioxide and from about 0.4 to 3.0 weight percent of a tablettinglubricant.
 8. A constant order release solid oral dosage formulation ofquinidine or a pharmaceutically acceptable salt thereof comprising: atherapeutically effective amount of quinidine or a pharmaceuticallyacceptable salt thereof; from 0.5 to 6.0 weight percent of ethylcellulose; from about 2.5 to 35 weight percent of a hydrogenatedvegetable oil; from about 1 to 20 weight percent ofcarboxypolymethylene; from about 0.5 to 4.0 weight percent of fumedsilicon dioxide; and from about 0.4 to 3.0 weight percent of atabletting lubricant.